The ability to prepare anthrax spores inexpensively and deliver them in an aerosol form, and the high mortality rate of inhalation anthrax, has made Bacillus anthracis one of the most feared agents of biological warfare and terrorism. Despite recent advances in understanding anthrax, no sustained effort has been made to develop new prophylactic or therapeutic agents to protect or treat against the disease. The current anthrax vaccine (AVA) consists of an alum-adsorbed culture filtrate, principally containing the anthrax toxin protective antigen (PA), from an attenuated strain of B. anthracis. Immunization with AVA requires multiple doses over 18 months and occasionally produces local reactogenicity in vaccinees. Accordingly, there is a critical requirement for an improved anthrax vaccine. The delivery of foreign antigens using live vectors is well suited for vaccines against diseases in which a rapid immune response against an antigen(s) is important for protection. The goal of this proposal is to evaluate the potential of live, attenuated strains of Vibrio cholerae and Salmonella typhimurium expressing PA, as improved anthrax vaccines. The Specific Aims of this project are to (1) construct attenuated V. cholerae and S. typhimurium vectors expressing recombinant PA, (2) evaluate the colonization and immunogenicity of (1) in pre-clinical models, and (3) evaluate the efficacy of (1) using anthrax toxin challenge in appropriate animal models. The successful accomplishment of these aims will provide new anthrax vaccines with the potential to confer protective immunity by oral immunization in humans.